Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that form transmembrane, cation- permeable channels. The (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazole) propionic acid (AMPA) subtype of iGluRs (AMPAR) is essential for the fast excitatory neurotransmission in the central nervous system (CNS). Malfunction of AMPARs has been implicated in several neurodegenerative diseases such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), as well as other neurological diseases such as cognitive deficits, epilepsy, schizophrenia, and mood disorders. For AMPARs as well as other iGluR subfamilies, active channels are tetramers exclusively formed by assembly of subunits within the same subfamily, a molecular process principally controlled by the extracellular amino-terminal domain (ATD). This phenomenon serves to control the permeation and kinetic properties of iGluR ion channels and is thus critical for maintaining normal physiological function of iGluRs. The goals of this proposal are to understand the molecular mechanisms by which the ATD guides subfamily-specific iGluR assembly. The specific aims are: (1) we will determine the crystal structures of the ATD of AMPARs; (2) we will characterize the role of the ATD in functional assembly of homomeric and heteromeric AMPAR channels; and (3) we will characterize the underlying mechanism by which ATDs guide subfamily-specific dimer-dimer association of iGluRs. The proposed study should provide a better understanding of the molecular principles governing iGluR assembly and function which could ultimately lay groundwork for future therapeutic interventions. Furthermore, molecular mechanisms governing iGluR assembly could be applicable for studying other multimeric ion channels/receptors, such as potassium channels, cyclic nucleotide-gated channels, nicotinic acetylcholine receptors, GABA receptors and others. Aberrant structure or function of these receptors/channels has been linked to many human neurological and psychiatric diseases.